Although a large number of DNA clones exist which cover many of the genes of the human major histocompatibility complex (MHC), a number of large gaps exist, including the 275-300 kb region of DNA between human leucocyte antigen (HLA)-DR and the complement genes. The MHC encodes genes determining susceptibility to disease, including juvenile-onset diabetes, gluten- sensitive enteropathy, and the blistering skin disease pemphigus vulgaris. These susceptibility genes are expected to include not only identified genes (class I and II HLA, complement factors 2, B, and 4, tumor necrosis factor alpha, and 21 hydroxylase), but other as-yet-unidentified genes in this region of extended haplotype which includes 2500 kilobases of DNA. This proposal describes the preparation of a derivative of the plasmid pYAC3 containing unique Mlu I and Sac II sites, and the cloning of overlapping Mlu I- and Sac II-restriction fragments from the HLA-DR-complement gap as yeast artificial chromosomes (YAC). We envisage potential applications of subclones for human genetics, clinical and forensic.